The Stress-Sensing Domain Of Activated Ire1 Alpha Forms Helical Filaments In Narrow Er Membrane Tubes

The signaling network of the unfolded protein response (UPR) adjusts the protein-folding capacity of the endoplasmic reticulum (ER) according to need. The most conserved UPR sensor, IRE1 alpha, spans the ER membrane and activates through oligomerization. IRE1 alpha oligomers accumulate in dynamic foci. We determined the in situ structure of IRE1 alpha foci by cryogenic correlated light and electron microscopy combined with electron cryo-tomography and complementary immuno-electron microscopy in mammalian cell lines. IRE1 alpha foci localized to a network of narrow anastomosing ER tubes (diameter, similar to 28 nm) with complex branching. The lumen of the tubes contained protein filaments, which were likely composed of arrays of IRE1a lumenal domain dimers that were arranged in two intertwined, left-handed helices. This specialized ER subdomain may play a role in modulating IRE1 alpha signaling.